Affiliations

1 Center for Innovation in Mental Health, Academic Unit of Psychology, and Clinical and Experimental Sciences (CNS and Psychiatry), Faculty of Medicine, University of Southampton, Southampton, UK; Solent NHS Trust, Southampton, UK; New York University Child Study Center, New York, NY, USA; Division of Psychiatry and Applied Psychology, School of Medicine, University of Nottingham, Nottingham, UK.

2 Department of Child and Adolescent Psychiatry, King's College London, and Institute of Psychiatry, Psychology and Neuroscience, and National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre, London, UK.

10 Division of Psychiatry and Applied Psychology, School of Medicine, University of Nottingham, Nottingham, UK; NIHR Nottingham Biomedical Research Centre, NIHR MindTech MedTech and In-vitro Diagnostic Cooperative, and Centre for ADHD and Neurodevelopmental Disorders Across the Lifespan (CANDAL), Institute of Mental Health, University of Nottingham, Nottingham, UK.

11 WHO Collaborating Centre for Research and Training in Mental Health and Service Evaluation, Department of Neuroscience, Biomedicine, and Movement Sciences, Section of Psychiatry, University of Verona, Verona, Italy.

13 Cochrane Schizophrenia Group, Division of Psychiatry and Clinical Psychology, School of Medicine, University of Nottingham, Nottingham, UK; Research Center for Modeling in Health, Institute for Future Studies in Health, Kerman University of Medical Sciences, Kerman, Iran.

Affiliations

1 Center for Innovation in Mental Health, Academic Unit of Psychology, and Clinical and Experimental Sciences (CNS and Psychiatry), Faculty of Medicine, University of Southampton, Southampton, UK; Solent NHS Trust, Southampton, UK; New York University Child Study Center, New York, NY, USA; Division of Psychiatry and Applied Psychology, School of Medicine, University of Nottingham, Nottingham, UK.

2 Department of Child and Adolescent Psychiatry, King's College London, and Institute of Psychiatry, Psychology and Neuroscience, and National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre, London, UK.

10 Division of Psychiatry and Applied Psychology, School of Medicine, University of Nottingham, Nottingham, UK; NIHR Nottingham Biomedical Research Centre, NIHR MindTech MedTech and In-vitro Diagnostic Cooperative, and Centre for ADHD and Neurodevelopmental Disorders Across the Lifespan (CANDAL), Institute of Mental Health, University of Nottingham, Nottingham, UK.

11 WHO Collaborating Centre for Research and Training in Mental Health and Service Evaluation, Department of Neuroscience, Biomedicine, and Movement Sciences, Section of Psychiatry, University of Verona, Verona, Italy.

13 Cochrane Schizophrenia Group, Division of Psychiatry and Clinical Psychology, School of Medicine, University of Nottingham, Nottingham, UK; Research Center for Modeling in Health, Institute for Future Studies in Health, Kerman University of Medical Sciences, Kerman, Iran.

Abstract

Background:
The benefits and safety of medications for attention-deficit hyperactivity disorder (ADHD) remain controversial, and guidelines are inconsistent on which medications are preferred across different age groups. We aimed to estimate the comparative efficacy and tolerability of oral medications for ADHD in children, adolescents, and adults.

Methods:
We did a literature search for published and unpublished double-blind randomised controlled trials comparing amphetamines (including lisdexamfetamine), atomoxetine, bupropion, clonidine, guanfacine, methylphenidate, and modafinil with each other or placebo. We systematically contacted study authors and drug manufacturers for additional information. Primary outcomes were efficacy (change in severity of ADHD core symptoms based on teachers' and clinicians' ratings) and tolerability (proportion of patients who dropped out of studies because of side-effects) at timepoints closest to 12 weeks, 26 weeks, and 52 weeks. We estimated summary odds ratios (ORs) and standardised mean differences (SMDs) using pairwise and network meta-analysis with random effects. We assessed the risk of bias of individual studies with the Cochrane risk of bias tool and confidence of estimates with the Grading of Recommendations Assessment, Development, and Evaluation approach for network meta-analyses. This study is registered with PROSPERO, number CRD42014008976.

Findings:
133 double-blind randomised controlled trials (81 in children and adolescents, 51 in adults, and one in both) were included. The analysis of efficacy closest to 12 weeks was based on 10 068 children and adolescents and 8131 adults; the analysis of tolerability was based on 11 018 children and adolescents and 5362 adults. The confidence of estimates varied from high or moderate (for some comparisons) to low or very low (for most indirect comparisons). For ADHD core symptoms rated by clinicians in children and adolescents closest to 12 weeks, all included drugs were superior to placebo (eg, SMD -1·02, 95% CI -1·19 to -0·85 for amphetamines, -0·78, -0·93 to -0·62 for methylphenidate, -0·56, -0·66 to -0·45 for atomoxetine). By contrast, for available comparisons based on teachers' ratings, only methylphenidate (SMD -0·82, 95% CI -1·16 to -0·48) and modafinil (-0·76, -1·15 to -0·37) were more efficacious than placebo. In adults (clinicians' ratings), amphetamines (SMD -0·79, 95% CI -0·99 to -0·58), methylphenidate (-0·49, -0·64 to -0·35), bupropion (-0·46, -0·85 to -0·07), and atomoxetine (-0·45, -0·58 to -0·32), but not modafinil (0·16, -0·28 to 0·59), were better than placebo. With respect to tolerability, amphetamines were inferior to placebo in both children and adolescents (odds ratio [OR] 2·30, 95% CI 1·36-3·89) and adults (3·26, 1·54-6·92); guanfacine was inferior to placebo in children and adolescents only (2·64, 1·20-5·81); and atomoxetine (2·33, 1·28-4·25), methylphenidate (2·39, 1·40-4·08), and modafinil (4·01, 1·42-11·33) were less well tolerated than placebo in adults only. In head-to-head comparisons, only differences in efficacy (clinicians' ratings) were found, favouring amphetamines over modafinil, atomoxetine, and methylphenidate in both children and adolescents (SMDs -0·46 to -0·24) and adults (-0·94 to -0·29). We did not find sufficient data for the 26-week and 52-week timepoints.

Interpretation:
Our findings represent the most comprehensive available evidence base to inform patients, families, clinicians, guideline developers, and policymakers on the choice of ADHD medications across age groups. Taking into account both efficacy and safety, evidence from this meta-analysis supports methylphenidate in children and adolescents, and amphetamines in adults, as preferred first-choice medications for the short-term treatment of ADHD. New research should be funded urgently to assess long-term effects of these drugs.

Funding:
Stichting Eunethydis (European Network for Hyperkinetic Disorders), and the UK National Institute for Health Research Oxford Health Biomedical Research Centre.

Figures

Figure 1

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Selection of studies for inclusion…

Figure 1

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Selection of studies for inclusion *The main reasons for exclusion included open-label or…

Figure 1

Selection of studies for inclusion *The main reasons for exclusion included open-label or single-blind studies, studies including patients with comorbid disorders, and combination therapy trials. We only searched for completed trials, which removed ongoing studies, particularly from clinicaltrials.gov.

Figure 2

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Network of eligible comparisons for…

Figure 2

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Network of eligible comparisons for efficacy and tolerability The width of the lines…

Figure 2

Network of eligible comparisons for efficacy and tolerability The width of the lines is proportional to the number of trials comparing every pair of treatments, and the size of every circle is proportional to the number of randomly assigned participants (sample size). The number of trials for pairs of treatments ranged from 22 (eg, studies of tolerability of methylphenidate vs placebo in children and adolescents) to one (several comparisons).

Figure 3

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Forest plots of network meta-analysis…

Figure 3

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Forest plots of network meta-analysis results Plots include all trials for efficacy and…

Figure 3

Forest plots of network meta-analysis results Plots include all trials for efficacy and tolerability and are compared with placebo as reference. No data for clonidine and guanfacine in adults are reported because no studies identified by our search tested these two drugs in adults. ADHD=attention-deficit hyperactivity disorder. OR=odds ratio. SMD=standardised mean difference.

Figure 4

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Two-dimensional graphs of efficacy versus…

Figure 4

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Two-dimensional graphs of efficacy versus tolerability in studies in children and adolescents and…

Figure 4

Two-dimensional graphs of efficacy versus tolerability in studies in children and adolescents and adults Effect sizes for individual drugs are represented by coloured nodes, with bars representing corresponding 95% CIs.